Methods compositions and devices utilizing stinging cells/capsules for delivering a therapeutic or a cosmetic agent into a tissue

ABSTRACT

A composition of matter including a therapeutic or a cosmetic agent and at least one stinging capsule and methods of use are described.

FIELD AND BACKGROUND OF THE INVENTION

[0001] The present invention relates to stinging cells or capsules andto the use thereof in compositions, devices and methods for delivering atherapeutic, cosmetic or diagnostic agent into a tissue. Moreparticularly, the present invention relates to the use of stinging cellsor capsules as transdermal/intradermal, transmembranal or transcuticulardelivery devices.

[0002] Therapeutic agents such as drugs are a mainstay of modem medicineand are used for the prevention, diagnosis, alleviation, treatment, orcure of diseases.

[0003] Biological, biochemical and/or physical barriers often limitdelivery of therapeutic agents to target tissue. For example, skinand/or various organ membranes are physical barriers, which must betraversed by a topically administered drug targeted at internal tissues.Orally administered drugs must be resistant to the low pH conditions anddigestive enzymes present in the gastrointestinal (GI) tract.

[0004] To traverse such barriers, drugs targeted at internal tissues areoften administered via a transdermal injection, using a syringe and aneedle or other mechanical devices. A transdermal injection deliversdrugs into the subcutaneous space thus traversing the epidermis—dermislayers.

[0005] Anatomically, the skin of a human body is subdivided into threecompartments: an epidermis, a dermis and a subcutaneous layer, of whichthe epidermis plays a key role in blocking drug delivery via the skin(the dourest layer of the epidermis is the stratum corneum which iscalled also the horny layer). The epidermis is 0.1 mm or more inthickness and consists mainly of protein surrounded by lipid, thusrendering the epidermis hydrophobic.

[0006] Although the syringe and needle is an effective delivery device,it is sensitive to contamination, while use thereof is often accompaniedby pain and/or bruising. In addition, the use of such a device isaccompanied by risk of accidental needle injury to a health careprovider.

[0007] Mechanical injection devices based on compressed gasses have beendeveloped to overcome the above-mentioned limitations of syringe andneedle devices. Such devices typically utilize compressed gas (such as,helium or carbon dioxide) to deliver medications at high velocitythrough a narrow aperture.

[0008] Although such devices traverses some of the limitations mentionedabove, their efficiency is medication dependent, and their use can leadto pain, bruising and lacerations.

[0009] Other less common delivery methods utilize a pulsed Yag laser topunctuate the stratum corneum in order to deliver medication viadiffusion and enhancement of ionic compound flux across the skin by theapplication of an electric current. Although such methods are effectivein delivering small charged molecules, a danger of skin bums accompaniestheir use.

[0010] Non-invasive methods, which overcome some of the limitationsinherent to the invasive delivery methods described above, have alsobeen described. Such methods utilize preparations, which include anactive ingredient disposed within lipid vehicles (e.g., liposomes) ormicelles or accompanied with skin permeation agent such that absorptionof the active ingredient through the skin is enhanced. Such preparationscan be directly applied to a skin region or delivered via transdermaldevices such as membranes, pressure-sensitive adhesive matrices and skinpatches.

[0011] In transdermal delivery, the active ingredient penetrates theskin and enters the capillary blood or the lymph circulation system,which carries the drug to the target organ or to the tissue or has alocal effect.

[0012] For several years, transdermal drug delivery systems have beenemployed to effectively introduce a limited number of drugs throughunbroken skin. Aside from comfort and convenience, transdermal systemsavoid the barriers, delivery rate control problems and potentialtoxicity concerns associated with traditional administration techniques,such as oral, intramuscular or intravenous delivery.

[0013] Although transdermal delivery offers an alternative to someinvasive delivery methods, the efficiency thereof is affected by thephysical and chemical properties of a drug and physiological orpathological parameters such as the skin hydration, temperature,location, injury, and the body metabolism.

[0014] To overcome the limitations of invasive and non-invasive deliverydevices, the present inventors propose the use of “stinging cells” (e.g.cnidocytes, nematocytes and the like) or “stinging capsules” (e.g.,cnidocysts, nematocysts and polar capsules) isolated therefrom fortissue delivery of a therapeutic or cosmetic agents.

[0015] Cnidaria (hydras, sea anemones, jellyfish and corals) are aquaticanimals, which possess a variety of compounds which are stored anddelivered via specialized capsules (cnidocysts), which form a part ofspecialized cells termed stinging cells (cnidocytes, nematocytes,ptychocytes and the like). The stinging capsules act as microscopicsyringes and serve as a prey or defense mechanism. The Cnidaria familywhich encompasses 10,000 known species, includes sedentary single orcolonial polyps and pelagic jellyfish. In some of these species,cnidocytes account for more than 45% of the cells present (Tardent1995).

[0016] As shown in FIGS. 1a-d, a cnidocyst is a hardened dense capsule,filled with liquid containing a highly folded inverted tubule whichsometimes features specialized structures such as shafts, barbs, spines,and/or stylets. In nature, the cnidocyst discharges and releases itstubule (FIG. 1d) into tissue following physical or chemical triggering.

[0017] Discharge is initiated by a rapid osmotic influx of water whichgenerates an internal hydrostatic (liquid) pressure of 150 atmospheresforcing capsule rupture and ejection of the tubule (Holstein and Tardent1984). During ejection, the long coiled and twisted tubule is avertedand its length increases by 95 percent. Accelerating at 40,000 g, thetubule untwists to generate a torque force, which rotates the tubuleseveral times around its axis. These mechanical processes generate apowerfill driving force, which enables efficient delivery of thecompounds, the toxins and enzymes stored within the capsule (Lotan etal. 1995, 1996; Tardent 1995). This process, which occurs withinmicroseconds, is among the most rapid exocytosis events in biology(Holstein and Tardent 1984).

[0018] There are at least three dozen known types of cnidocysts (alsotermed cnidae) including more than 30 varieties of nematocysts found inmost Cnidaria and spirocysts, and ptychocysts found mainly in theCnidaria class Anthozoa (Mariscal 1974).

[0019] As is further detailed herein, the present invention utilizesstinging cells such as cnidocytes, or stinging capsules (cnidocysts)isolated therefrom for efficiently delivering agents into a tissue whilebeing devoid of the limitations inherent to prior art invasive ornon-invasive delivery devices and compositions.

SUMMARY OF THE INVENTION

[0020] According to one aspect of the present invention there isprovided a composition of matter comprising a therapeutic or a cosmeticagent and at least one stinging capsule.

[0021] According to another aspect of the present invention there isprovided a pharmaceutical composition comprising as an active ingredienta therapeutic or cosmetic agent, at least one stinging capsule and apharmaceutically acceptable carrier.

[0022] According to yet another aspect of the present invention there isprovided a delivery device comprising: (a) at least one stinging capsulecapable of delivering upon discharge liquid disposed in or around the atleast one stinging capsule into a tissue; and (b) a support being for:(i) supporting the at least one stinging capsule; and (ii) applying theat least one stinging capsule to an outer surface of the tissue.

[0023] According to further features in preferred embodiments of theinvention described below, the at least one stinging capsule includes aplurality of stinging capsules attached to the support in a manner so asto form a tattoo making device.

[0024] According to still another aspect of the present invention thereis provided a method of delivering a therapeutic or a cosmetic agentinto a tissue, the method comprising the steps of: (a) applying acomposition of matter including the therapeutic or cosmetic agentdisposed in or around at least one stinging capsule to an outer surfaceof the tissue; and (b) triggering a discharge of the at least onestinging capsule to thereby deliver the therapeutic or the cosmeticagent into the tissue.

[0025] According to an additional aspect of the present invention thereis provided a method of delivering a therapeutic or a cosmetic agentinto a tissue, the method comprising the steps of: (a) applying acomposition including, as an active ingredient, at least one therapeuticor cosmetic agent onto an outer surface of the tissue; and (b) applyingat least one stinging capsule to the outer surface of the tissue; and(c) triggering a discharge of the at least one stinging capsule tothereby deliver the therapeutic or the cosmetic agent into a tissue.

[0026] According to yet an additional aspect of the present inventionthere is provided a method of preparing a delivery capsule, the methodcomprising the steps of: (a) isolating an intact stinging capsule froman organism; and (b) treating the stinging capsule under conditionswhich inactivate an endogenous toxin stored in the stinging capsule yetdo not trigger discharge or breakdown of the stinging capsule to therebyobtain the delivery capsule.

[0027] According to still an additional aspect of the present inventionthere is provided a delivery device comprising a stinging capsule,wherein an endogenous toxin stored by the isolated stinging capsule isnon-functional.

[0028] According to further features in preferred embodiments of theinvention described below, the therapeutic or cosmetic agent is disposedin a liquid surrounding, or stored within, the at least one stingingcapsule.

[0029] According to still further features in the described preferredembodiments the therapeutic agent is selected from the group consistingof a drug, a nucleic acid construct, a vaccine, a hormone, an enzyme andan antibody.

[0030] According to still further features in the described preferredembodiments the therapeutic agent is a prodrug activatable prior to,during or following discharge of the at least one stinging capsule.

[0031] According to still further features in the described preferredembodiments the cosmetic agent is selected from the group consisting ofa cosmetic dye, an anti wrinkling agent, an anti-acne agent, a vitamin,a skin peel agent, a hair follicle stimulating agent and a hair folliclesuppressing agent.

[0032] According to still further features in the described preferredembodiments the stinging capsule can be an isolated stinging capsule orit can form a part of an isolated stinging cell.

[0033] According to still further features in the described preferredembodiments the at least one stinging capsule is capable of deliveringthe therapeutic or cosmetic agent into a tissue.

[0034] According to still further features in the described preferredembodiments the endogenous toxin naturally stored within the at leastone stinging capsule is substantially non-toxic to mammals.

[0035] According to still further features in the described preferredembodiments the endogenous toxin is non-functional.

[0036] According to still further features in the described preferredembodiments the at least one stinging capsule is derived from anorganism of a class selected from the group consisting of Anthozoa,Hydrozoa and Scyphozoa.

[0037] According to still further features in the described preferredembodiments the at least one stinging capsule is derived from a stingingcell of an organism of a phylum selected from the group consisting ofCnidaria, Dinoflagellata and Myxozoa.

[0038] According to still further features in the described preferredembodiments the at least one stinging cell forms a part of at least atentacle portion of an organism of the phylum Cnidaria.

[0039] According to still further features in the described preferredembodiments the pharmaceutically acceptable carrier is selected from thegroup consisting of an aqueous solution, a gel, and an oil and semisolid formulation.

[0040] According to still further features in the described preferredembodiments the device further comprising a mechanism for triggering thedischarge of the at least one stinging capsule.

[0041] According to still further features in the described preferredembodiments the mechanism is selected from the group consisting of achemical triggering mechanism and an electrical triggering mechanism.

[0042] According to still further features in the described preferredembodiments the support is selected from the group consisting of apatch, a foil, a plaster and a film.

[0043] According to still further features in the described preferredembodiments the step of triggering is effected by a change in pH, achemical substance, a mechanical force or contact between the at leastone stinging capsule and the outer surface of the tissue.

[0044] According to still further features in the described preferredembodiments the organism is of a phylum selected from the groupconsisting of Cnidaria, Dinoflagellata and Myxozoa.

[0045] According to still further features in the described preferredembodiments the step of treating the stinging capsule under conditionswhich inactivate an endogenous toxin stored in the stinging capsule yetdo not trigger discharge or breakdown of the stinging capsule to therebyobtain the delivery capsule) is effected by incubating the stingingcapsule at a temperature of 37-45° C. for at least two hours.

[0046] The present invention successfully addresses the shortcomings ofthe presently known configurations by providing a natural source fordelivering therapeutic and cosmetic agents. By exploiting one of themost efficient system that exist in biology it is possible to usestinging capsules as delivery capsules for drugs, vaccines, antibodies,DNA constructs and other agents.

BRIEF DESCRIPTION OF THE DRAWINGS

[0047] The invention is herein described, by way of example only, withreference to the accompanying drawings. With specific reference now tothe drawings in detail, it is stressed that the particulars shown are byway of example and for purposes of illustrative discussion of thepreferred embodiments of the present invention only, and are presentedin the cause of providing what is believed to be the most useful andreadily understood description of the principles and conceptual aspectsof the invention. In this regard, no attempt is made to show structuraldetails of the invention in more detail than is necessary for afundamental understanding of the invention, the description taken withthe drawings making apparent to those skilled in the art how the severalforms of the invention may be embodied in practice.

[0048] In the drawings:

[0049]FIGS. 1a-d illustrate the structure and release mechanism of acnidocyst.

[0050]FIG. 2a is a schematic illustration of a delivery device accordingto the teachings of the present invention.

[0051]FIG. 2b is a prior art scanning electron micrograph showingstinging cells of Cyanea capillata following activation via human skincontact.

[0052]FIG. 3 is a microscope image of capsules (stinging capsules)isolated from Rhopilema nomadica tentacles.

[0053]FIG. 4 is a microscope image of capsules isolated from Rhopilemanomadica tentacles. The folded tubule inside some of the capsules ismarked with an arrow.

[0054]FIG. 5 is a microscope image of capsules isolated from Rhopilemanomadica following discharge activation with NaSCN.

[0055]FIG. 6 illustrates capsules isolated from Rhopilema nomadica(Arrow B) and loaded with a pigment (arrow A).

[0056]FIG. 7 illustrates capsules isolated from Rhopilema nomadica andloaded with a pigment of a molecular weight of 306 daltons, prior to(arrow A) and following (arrow B) discharge activation with NaSCN.

[0057]FIG. 8 illustrates capsules isolated from Rhopilema nomadica andloaded with a pigment of a molecular weight of 306 daltons, prior to(arrow A) and following (arrow B) discharge activation with NaSCN.

[0058]FIG. 9 illustrates dermal penetration of a tubule discharged froman isolated cnidocyst (tubule indicated by arrows).

[0059]FIG. 10 illustrates an intraepidermal injection of a pigment (306daltons) via a preloaded cnidocyst (arrow indicates region of delivery).

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0060] The present invention is of compositions, devices and methodsutilizing stinging cells or capsules, which can be used, for example,for transdermal/intradermal, transmucosal or transcuticular delivery ofan agent, such as for example a biologically active agent. Specifically,the present invention relates to the use of stinging cells (cnidocytes)or to stinging capsules isolated therefrom (cnidocysts) fortransdermal/intradermal, transmucosal, transcuticular or transmembranaldelivery of a therapeutic or a cosmetic agent.

[0061] The principles and operation of the present invention may bebetter understood with reference to the drawings and accompanyingdescriptions.

[0062] Before explaining at least one embodiment of the invention indetail, it is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement of thecomponents set forth in the following description or illustrated in thedrawings. The invention is capable of other embodiments or of beingpracticed or carried out in various ways. Also, it is to be understoodthat the phraseology and terminology employed herein is for the purposeof description and should not be regarded as limiting.

[0063] Throughout history man has exploited or imitated naturallyoccurring processes, e.g., biological processes, for the advancement ofscientific fields such as medicine or engineering. As is furtherdescribed herein, the present invention exploits the unique deliverymechanism of stinging cells, such as cnidocytes or isolated stingingcapsules such as cnidocysts, for the delivery of therapeutic, diagnosticor cosmetic agents into tissues of a metazoan organism, such as, forexample, a mammal.

[0064] By utilizing isolated stinging cells or capsules for delivery ofan agent of choice, the present invention enables easy, efficient andpainless delivery of a therapeutic or a cosmetic agents into, forexample, mammalian tissues such as for example dermal tissues. The useof such stinging cells or capsules for delivery enables an accurate andlocalized delivery of precise dosages while being devoid of the pain anddiscomfort associated with other invasive delivery methods. In addition,by utilizing stinging cells or capsules for delivery, the presentinvention enables precise control over the depth of penetration and assuch the tissue region of delivery. Tubules are capable of penetratingthrough tissue to a depth of up to 800 microns, depending on the tissueand stinging cell types from which they are discharged. As such,different stinging cell/capsule types can be utilized for delivery intodifferent tissue regions or depths. For example, for tattoo injection, astinging cell or capsule which can deliver the cosmetic dye into thearea between the epidermis and the dermis is preferred.

[0065] It should be noted that unlike any other delivery devicescurrently in use, various types of stinging cells or capsules are ableto efficiently and accurately deliver their contents directly into theepidermis. Currently, epidermal delivery of therapeutic compounds isgenerally effected by non specific diffusion which is slow and requireslarge concentrations of the therapeutic agent.

[0066] Thus, the efficiency and accuracy of the delivery device of thepresent invention makes it highly suitable for the treatment of, forexample, psoriasis, where the depth of delivery is of crucialimportance.

[0067] As used herein, the phrase “stinging cell” refers to thespecialized cells (e.g. cnidocytes or nematocytes) present in, forexample, all members of the phylum Cnidaria, Myxozoa, andDinoflagellata. A stinging cell contains the “stinging capsule” whichhouses the delivery tubule.

[0068] The Cnidaria phylum represents about 10,000 species includingsedentary single or colonial polyps and pelagic jellyfish, however only15 species store and deliver compounds known to be irritating or toxicto mammals. In some animals cnidocytes consist for more than 45% of thecells present (Tardent 1995). There are at least three-dozen types ofcnidae described in the literature including more than 30 varieties ofnematocysts found in most Cnidaria and spirocysts and ptychocysts foundmainly in the Cnidaria class Anthozoa (Mariscal 1974).

[0069] Although, cnidae are characteristic of Cnidaria they can be foundin two other groups: the Myxozoa and the Dinoflagellata. Until recentlyMyxozoan were classified as a protozoa parasite however, based onphylogenetic analyses of 18S ribosomal RNA sequences it was suggestedthat the Myxozoa should be grouped in the metazoan phylum (Smothers etal. 1994). Anderson and Okamura (Anderson et al. 1998) placed theMyxozoa with the Bilateria, whereas Siddall et al. suggested that theMyxozoa belongs as a group to the Cnidaria phylum (Siddall et al. 1995).Myxozoan cnidae are very similar in their morphogenesis and maturestructure to the Cnidarian cnidae. Formation of cnidae can be found inthe protozoa Dinoflagellata, specifically in the colonial DinoflagellatePolykrikos (Westfall et al. 1983). Polykrikos produces 2 distinctorganelles: the nematocyst and the taeniocyst that are organized as acomplex. The Polykrikos nematocyst (cnida) has a similar maturestructure of Cnidarian cnida.

[0070] Thus, according to one aspect of the present invention there isprovided a composition of matter, which includes a therapeutic agentsuch as a drug, antibody, protein, DNA construct and the like or acosmetic agent such as a cosmetic dye, an anti-wrinkling agent, avitamin, a skin peel agent, a hair follicle stimulating agent, a hairfollicle suppressing agent and the like, and at least one stingingcapsule.

[0071] The stinging capsule according to the teachings of the presentinvention can be an isolated stinging capsule or alternatively it canform a part of a stinging cell. In any case, the stinging capsule orcell is derived from an organism of the phylum Cnidaria, Myxozoa, orDinoflagellata.

[0072] The stinging cell or capsule utilized by the present invention ispreferably derived from an organism of the class Anthozoa, Hydrozoa orScyphozoa. More specifically, the stinging cell/capsule utilized by thepresent invention can be derived from, for example, subclassesHexacorallia or Octocorallia of the class Anthozoa, (mostly sea anemoneand corals), subclasses Siponophora or Hydroida of the class Hydrozoa,or from subclasses Rhisostomeae or Semastomeae of the class Scyphozoa.

[0073] Stinging capsules from such organisms include toxins, which arenon-toxic to humans, and other mammals. As such, these stinging cells orcapsules isolated therefrom are ideally suited for safe and efficientdelivery of a therapeutic or cosmetic agent into mammalian tissue.

[0074] It will be appreciated that the use of stinging cells fromorganisms which sequester toxins that are not fatal but cause only minorirritations to, for example, mammals, is also envisioned by the presentinvention.

[0075] In addition, stinging cells from other sources can also beutilized by the present invention provided inactivation of theendogenous toxin is effected prior to use.

[0076] Such inactivation can be effected via one of several methods,including but not limited to, temperature or chemical denaturation,enzymatic inactivation or ligand inactivation (e.g., Fab fragment of anantibody).

[0077] As is further described in the Examples section, which follows,toxins endogenous to cnidocysts can be efficiently and easilyinactivated by incubating isolated cnidocysts at 45° C. for severalhours. Alternatively, incubation at a high temperature of 70-95° C. forseveral minutes can also be utilized by the present invention.

[0078] As demonstrated herein, incubation of cnidocysts at 45° C. for 22hours does not damage or trigger activation of the cnidocyst. Suchconditions are effective in denaturing polypeptides stored within thecnidocyst, such as the polypeptide toxins and enzymes delivered by thetubule of the cnidocyst. It will be appreciated that since organisms of,for example, the phylum Cnidaria habitat aquatic environments, which arecharacterized by temperatures well below 30° C., polypeptides storedwithin their stinging capsules can be denatured via incubation intemperatures well above 30° C.

[0079] The stinging cell or the stinging capsule of the presentinvention can be isolated from a cell extract prepared from organs orparts of an organism, which contain the stinging cells (for example awhole hydra or tentacles). Alternatively, stem cells, which give rise tocnidocytes or cnidocysts, can be isolated and cultured or utilizeddirectly. It will be appreciated that the composition of matter of thepresent invention can also directly utilize the organs, tentacles, orparts of an organism, and the whole organism (hydra for example), whichcontain the stinging cells without the need for isolating individualstinging cells or for isolating the capsules from the cells.

[0080] Thus, according to the teachings of the present inventionisolated and optionally pretreated stinging cells or stinging capsulescan be utilized for delivering a therapeutic or cosmetic agent into atissue region of an individual. Preparation of such delivery devices isdescribed in detail in Examples 1 and 3 of the Examples section, whichfollows.

[0081] Delivery of a therapeutic or cosmetic agent according to thepresent invention can be effected by applying the composition of matterdescribed above to an outer surface of the tissue (e.g., skin).Following application, the stinging cells or the isolated capsules aretriggered (as is further described hereinbelow) and the therapeutic orthe cosmetic agent is thereby delivered by the tubule into the tissue.

[0082] Alternatively, the therapeutic or cosmetic agent can be appliedonto the outer surface of the tissue, followed by application ofstinging cell(s) or stinging capsules to the same region. Upontriggering, the agent is pumped into the stinging cells or into thecapsules (as is further described herein) and the therapeutic or thecosmetic agent is delivered via the tubule into the tissue.

[0083] According to preferred embodiments of the present invention, thetherapeutic agent can be any biological active factor such as, forexample, a drug, a nucleic acid construct, a vaccine, a hormone, anenzyme, small molecules such as for example iodine or an antibody.Examples include, but are not limited to, antibiotic agents, freeradical generating agents, anti fungal agents, anti-viral agents,non-nucleoside reverse transcriptase inhibitors, protease inhibitors,non-steroidal anti inflammatory drugs, immunosuppressants,anti-histamine agents, retinoid agents, tar agents, antipuritic agents,hormones, psoralen, and scabicide agents. Nucleic acid constructsdeliverable by the present invention can encode polypeptides (such asenzymes ligands or peptide drugs), antisense RNA, or ribozymes.

[0084] The therapeutic agent can also be a prodrug, which is activatableprior to, during, or following discharge of the stinging capsule. Asused herein in the specification and in the claims section whichfollows, the term “prodrug” refers to an agent which is inactive butwhich is convertible into an active form via enzymatic, chemical orphysical activators.

[0085] A prodrug (for example an enzyme) can be activated just prior tostinging cell discharge by providing an activator compound (for examplean ion), which can be diffused or pumped (during discharge) into thecapsule. Alternatively, specific enzymes, molecules or pH conditionspresent in the target tissues, can activate the prodrug.

[0086] The cosmetic agent of the present invention can be, for example,an anti-wrinkling agent, an anti-acne agent, a vitamin, a skin peelagent, a hair follicle stimulating agent or a hair follicle suppressingagent. Using the stinging cells/capsules of the present invention a moreeffective delivery of such cosmetic agents can be effected. Examples ofcosmetic agents include, but are not limited to, retinoic acid and itsderivatives, salicylic acid and derivatives thereof, sulfur-containing Dand L amino acids and their derivatives and salts, particularly theN-acetyl derivatives, alpha-hydroxy acids, e.g., glycolic acid, andlactic acid, phytic acid, lipoic acid and many other agents which areknown in the art, such as, for example the hair follicle stimulating orsuppressing agents described hereinbelow.

[0087] In addition, stinging cells or isolated capsules injecting acosmetic dye can be utilized as a sterile, needle free and pain freemethod of producing permanent or transient tattoos. For such purposes, apredetermined pattern of stinging cells/capsules can be attached to asupport such as a plaster, foil or the like as described hereinabove.The stinging cells/capsules can be preloaded with a cosmetic dye orimmersed therein prior to, or during triggering activation (e.g., thecosmetic dye can be applied to the skin). Upon stinging cells/capsulesdischarge (via, for example, skin contact), the dye would penetrate intothe skin to form a predetermined dye pattern (tattoo).

[0088] According to one preferred embodiment of the present invention,the therapeutic or cosmetic agent is disposed within the liquid storedin the stinging cell or the stinging capsule. In such a case, thestinging cell or the isolated capsule is loaded with the therapeutic orcosmetic agent via any one of several methods generally known in the artsuch as, but not limited to, diffusion, electroporation, liposomefusion, microinjection and the like.

[0089] Alternatively and according to another preferred embodiment ofthe present invention, the therapeutic or cosmetic agent is disposed ina liquid surrounding the stinging cell or the isolated capsule. In sucha case, the stinging capsule's natural mechanism of osmoticallycollecting liquid from the environment following triggering (furtherdetailed in the background section hereinabove) pumps the therapeutic orcosmetic agent into the stinging cell just prior to or during thedischarge.

[0090] In any case, since a stinging capsule is highly permeable towater and molecules, therapeutic or cosmetic agent loading prior to orduring discharge can be easily achieved.

[0091] As is further described in Example 4 of the Examples section,which follows, a pigment disposed in water surrounding an isolatedstinging capsule easily penetrates the capsule via simple diffusion andthus can be discharged following activation.

[0092] Prior art studies which concentrated on deciphering thepermeability and functionality of stinging capsules have shown thatalkali ions, monovalent ions, divalent ions, or small organic cationssuch as Tris+ or choline+, penetrate cnidocysts and accumulate insidewithout affecting the properties of the stinging cell or capsule.Studies performed by Lubbock & Amos in order to understand the effect ofcalcium on capsule discharge (1981) have shown that in the predischargedstate the cnida wall is permeable to water and to charged molecules ofrelatively low molecular weight like bromophenol blue (MW 670) andfluoresceinate (MW 376). Hidaka, who investigated of the mechanism ofcapsule discharge (1992, 1993) demonstrated that cnidocysts stained withtoluidine blue (MW 306) released the blue stain through the tubule whendischarged leaving the capsule completely clear. Heeger et al., (1992)investigated the ability of different commercially available lotions toprotect human skin against stinging cell penetration.

[0093] Thus, short polypeptides, hormones, or any low molecule weightagents can be loaded into stinging cells through simple diffusion. Theseactive compounds can be stored in the stinging capsule and injected intothe target tissue upon discharge.

[0094] As mentioned hereinabove, during the discharge process, theimmediate liquid surrounding the stinging cell is pumped into thecapsule and than injected via the tubule. Since the surrounding liquidis pumped into the cnida under extremely high pressures over a shortperiod of time it is highly plausible that high molecular weightmolecules, such as polypeptides polynucleotides and other complexmolecules can penetrate the capsule and be delivered via the tubule upondischarge.

[0095] In any case, the composition of matter described above can bedirectly utilized to deliver the therapeutic or cosmetic agent intomammalian and other tissue by applying the stinging cells or capsulesisolated therefrom, which include the agent, or by co-applying the agentand 18 stinging cell/capsule onto a skin region of an individual (e.g. ahuman or livestock and other) and triggering discharge eitherautomatically (via contact with the tissue) or manually via anactivation mechanism which is described in detail hereinbelow.

[0096] Triggering the activation of the stinging cell/capsules thusleads to the subsequent transdermal/intradermal, transmucosal,transmembranal or transcuticular delivery of the therapeutic or cosmeticagent.

[0097] To stabilize the therapeutic or cosmetic agent and/or thestinging cell(s)/capsule(s) and to possibly enhance triggeringefficiency, the composition of matter of the present invention ispreferably included in a pharmaceutical composition.

[0098] Thus, according to another aspect of the present invention thereis provided a pharmaceutical composition, which includes, as an activeingredient, a therapeutic or cosmetic agent, at least one stingingcapsule (either isolated or forming a part of a stinging cell) and apharmaceutically acceptable carrier.

[0099] Hereinafter, the phrase “pharmaceutically acceptable carrier”refers to a carrier, which does not cause significant irritation to theindividual treated and does not abrogate the biological activity andproperties of the active ingredient.

[0100] Preferably, the pharmaceutically acceptable carrier does notaffect the ability of the stinging cells to discharge followingtriggering although in some instances, a pharmaceutically acceptablecarrier which inhibits triggering mediated by tissue contact can also beutilized by the present invention.

[0101] The pharmaceutical composition of the present invention includesa pharmaceutically acceptable carrier, which is formulated for topical,transmucosal or transnasal applications.

[0102] For topical application, the active ingredient and stingingcell(s)/capsule(s) may be suspended in hydrophilic or hydrophobic-basedcarrier such as a gel suitable for topical applications.

[0103] For topical, transmucosal or transnasal administration, theactive ingredient and stinging cells can be conveniently delivered inthe form of an aerosol spray presentation from a pressurized pack or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane or carbon dioxide. In the case of apressurized aerosol, the dosage unit may be determined by providing avalve to deliver a metered amount.

[0104] In any case, application of the composition to, for example, askin region leads to subsequent contact between the stingingcell(s)/capsule(s) and the skin the individual which contact triggersdischarge of the stinging cell/capsule and delivery of the activeingredient into for example, an epidermis or dermis tissue region of theindividual.

[0105] Although, for some applications, contact mediated dischargesuffices, such activation can be inefficient since it enables dischargeof only the portion of stinging cells, which come into physical contactwith the tissue following application.

[0106] To enable a more efficient and consistent discharge and thusdelivery of the active agent, the pharmaceutical composition of thepresent invention can include a pharmaceutically acceptable carrierwhich inhibits discharge of the stinging cell(s)/capsule(s) upon tissuecontact (e.g., skin contact). In such cases, the pharmaceuticalcomposition also includes a chemical activator, such as, for exampleNaSCN or EGTA, which can be applied prior to, or following, applicationof the pharmaceutical composition and which triggers discharge of thestinging cells. Chemical or electrical activation of discharge isadvantageous since it allows for simultaneous discharge of most if notall of the stinging cells of the pharmaceutical composition.

[0107] According to the teachings of the present invention, the stingingcells/capsules described above can also be utilized in a delivery deviceuseful for delivering a therapeutic or cosmetic agent into a tissueregion of an individual.

[0108] Thus, as specifically shown in FIG. 2a and according to yetanother aspect of the present invention there is provided a deliverydevice, which is referred to herein as device 10.

[0109] Device 10 includes at least one stinging cell/capsule 12 (severalare shown). Upon discharge, stinging cell/capsule 12 is capable ofdelivering (via it's tubule) liquid disposed in or around stingingcell/capsule 12 into a tissue region (as described hereinabove). Device10 further includes a support 14, which serves for supporting stingingcell/capsule 12 and for applying stinging cell/capsule 12 to an outersurface of the tissue region into which delivery is desired.

[0110] Device 10 can be utilized to deliver a therapeutic or a cosmeticagent, which is loaded into stinging cell(s)/capsule(s) 12 or disposedin a liquid surrounding stinging cell(s)/capsule(s) 12.

[0111] Support 14 can be, for example, a patch, a foil, a plaster or afilm or any material capable of supporting stinging cell(s)/capsule(s)12 in a manner suitable for application to, for example, a skin regionof the individual.

[0112] Stinging cells 12 can be secured to support 14 via, for example,biological glue (e.g. BIOBONDTM), polylysine, a mesh support or thelike.

[0113] Discharge of stinging cell(s)/capsule(s) 12 can be activated uponcontact with tissue as described above. For example, followingapplication of device 10, pressure can be exerted on support 14 thusforcing contact between stinging cells 12 and the tissue region therebyactivating discharge. Alternatively, discharge can be activated by amechanism 16 included within device 10.

[0114] Mechanism 16 can be an electrical or chemical activatingmechanism which when activated by a physician or by the individual to betreated, triggers simultaneous discharge of stinging cell(s)/capsule(s)12 preferably in a rapid and uniform manner.

[0115] Chemical triggering can be mediated by substances such as freeand conjugated N-acetylated sugars or low molecular weight aminocompounds which are known to be detected by at least two classes ofstinging cell chemoreceptors. FIG. 2b shows a prior art image ofstinging capsules isolated from Cyanea capillata following activation bycontacting human skin.

[0116] As is further described in Example 2 of the Examples sectionbelow, Sodium thiocyanate (NaSCN) is capable of triggering discharge ofcnidocysts. In addition, Lubbock and Amos (1981) have shown thatisolated cnida (cnidocysts) can discharge normally when placed inbuffered EGTA or 10 mM citrate solution; Weber (1989) demonstrated theeffect of dithioerthritol or proteases on discharging isolated cnida andHidaka (1993) discussed various agents which can trigger cnidadischarge.

[0117] Electrical triggering can be achieved via an electrical pulse of30 microseconds of approximately 20-30 Volts as is further described inthe literature (Holstein and Tardent 1984; Tardent and Holstein 1982).

[0118] As mentioned hereinabove, the present invention can be utilizedto deliver a variety of therapeutic agents. Such therapeutic agentscombined with the effective delivery obtainable via stingingcells/capsules can be utilized to treat a variety of disorders.

[0119] An example of a very common skin infection is acne, which involveinfestation of the sebaceous gland with p. acnes, as well Staphylococusaurus and pseudomonas. The disorder can be treated by anti-bacterialagents such as phenols, including cresols and resorcinols andantibiotics such as chloramphenicol, tetracyclines, synthetic andsemi-synthetic 22 penicillins, beta-lactames, quinolones,fluoroquinolnes, macrolide antibiotics, peptide antibiotics,cyclosporines, erytromycin and clindamycin.

[0120] Psoriasis, which is a common skin disorder can be treated byusing the present invention for accurate and efficient intraepidermaldelivery of steroidal anti-inflammatory agents or other known drugs withlimited skin permeability.

[0121] Fungal infections can also be treated via the pharmaceuticalcomposition or delivery device of the present invention. Superficialfungal infection of the skin is one of the commonest skin diseases seenin general practice. Dermatophytosis is probably the most commonsuperficial fungal infection of the skin. Candidiasis is an infectioncaused by the yeast like fungus Candida albicans or occasionally otherspecies of candida. Antifungal drugs, which are active againstdermatophytes and candida such as azoles, diazoles, triazoles,miconazole, fluconazole, ketoconazole, clotrimazole, itraconazolegriseofulvin, ciclopirox, amorolfine, terbinafine, Amphotericin B,potassium iodide, flucytosine (5FC) and any combination thereof at atherapeutically effective concentration can be deliveredintraepidermally via the delivery device or method of the presentinvention.

[0122] The present invention can be also used for delivering pigments,such as photosensitizers utilizable in photo dynamic therapy (PDT), intocells of skin cancer or other skin disorders. Photosensitizers arechemical compound which produce a biological effect uponphotoactivation, or a biological precursor of a compound that produces abiological effect upon photoactivation. Examples of photosensitizerswhich can be delivered by the stinging cells/capsules of the presentinvention include, but are not limited to, hematoporphyrins (Batlle 1993J. Photochem. Photobiol. Biol. 20:5-22 and Kessel 1988 Cancer Let.39:193-198), uroporphyrins and phthalocyanines (Kreimer-Bimbaum, 1989Seminars in Hematology 26:157-173), purpurins (Morgan et al. 1990Photochem. Photobiol. 51:589-592 and Kessel, 1989 Photochem. Photobiol.50:169-174), acridine dyes and bacteriochlorophylls (Beems et al. 1987Photochem. Photobiol. 46:639-643 and Kessel et al. 1989 Photochem.Photobiol. 49:157-160), and bacteriochlorins (Gurinovich et al. 1992 J.Photochem. Photobiol. Biol. 13:51-57). By enabling accurate andefficient delivery of photosensitizers, the present inventionsubstantially improves the efficiency of PDT.

[0123] Eye infections such as conjuctivitis, caused by bacteria such asstaphylococcus aureus, streptococcus pneumoniae, and haemophilusinfluenzae can be treated with antibiotic ointments, e.g., bacitracinwhich is delivered via the delivery device or method of the presentinvention.

[0124] Chronic rheumatic or arthritic conditions are usually treated byNSAIDs. Such as salicylic acid, or aspirin, and ibuprofen are well-knownexamples of NSAI drugs. Patients taking NSAIDs drugs orally face anincreased risk for peptic ulcers and gastrointestinal blood lossresulting in anaemia. Such adverse reactions especially plague patientstaking NSAIDs drugs over prolonged periods. Transdermal administrationof NSAIDs via the delivery device or method of the present inventionwill prevent the gastrointestinal complications. Transdermal drugdelivery according to the present invention provides other benefits suchas less frequent dosing; better controlled drug release, and a greaterability to target delivery to specific tissue sites.

[0125] Anaesthetics can be used for alleviating pain for example duringsuturing, or in infections, which are accompanied with pain sensation.Examples of topical anaesthetic drugs include without limitationbenzocaine, lidocaine, bupivacaine, chlorprocaine, dibucaine,etidocaine, mepivacaine, tetracaine, dyclonine, hexylcaine, procaine,cocaine, ketamine, pramoxine, phenol, and pharmaceutically acceptablesalts thereof all of which are deliverable via the delivery device ormethod of the present invention.

[0126] The stinging capsules or cells of the present invention can beused to treat hair loss, excessive hair growth, or discoloration of thehair.

[0127] For example, a hair follicle stimulating agent such ashinokitiol, or pantothenic acid can be delivered by the stingingcells/capsules of the present invention directly into the follicle inorder to stimulate hair growth. Allternatively, the stingingcells/capsules of the present invention can be utilized to deliver,directly into hair follicles, an hair follicle suppressing agent capableof suppressing hair growth. Examples of agents capable of suppressinghair growth include, but are not limited to, nonsteroidal suppressors ofangiogenesis and inhibitors of 5-alpha reductase, ornithinedecarboxylase, S-adenosylmethionine decarboxylase, gammaglutamyltranspeptidase, and transglutaminase.

[0128] The present invention can also be utilized to pigment hair colorby delivering, for example, melanin or tyrosinase, into the hairfollicle.

[0129] In addition to the above, the teachings of the present inventioncan also be utilized to deliver drugs into blood circulation via eithertransdermal delivery, which leads to diffusion into small capillaries orby applying the delivery device of the present invention to internalbody tissues.

[0130] In such cases, the present invention can be utilized to deliverdrugs such as hormones (e.g., insulin), antibiotics, cardiac drugs andthe like.

[0131] The stinging cells/capsules of the present invention can also beutilized for vaccination. Vaccine antigens can be delivered tospecialized immune cells underlying the skin or into blood circulation(as described above).

[0132] Absorption into the blood stream following transdermal deliverywill most likely result in transport of the antigen to the phagocyticcells of the liver, spleen, and bone marrow. Since such cells serve asantigen presenting cells, a strong immunogenic response will be elicitedleading to effective immunization.

[0133] Thus, the present invention overcomes the limitations of priorart devices and methods while providing a safe, efficient andcontamination risk free method for delivering agents across epidermalmucousal or membranal barriers.

[0134] Additional objects, advantages, and novel features of the presentinvention will become apparent to one ordinarily skilled in the art uponexamination of the following examples, which are not intended to belimiting. Additionally, each of the various embodiments and aspects ofthe present invention as delineated hereinabove and as claimed in theclaims section below finds experimental support in the followingexamples.

EXAMPLES

[0135] Reference is now made to the following examples, which togetherwith the above descriptions illustrate the invention in a non-limitingfashion.

Example 1 Isolation of Capsules

[0136] Fresh tentacles of Rhopilema nomadica were homogenized inseawater. 300 μl of the homogenate was added to 300 μl Percoll in amicrofuge tube. The tube was shaken over ice for 30 min and thencentrifuged for 10 minutes, at 1000 rpm. The pellet was washed 3 timeswith H₂O and resuspended in 50 μl H₂O. The tube was kept at 4° C. untiluse.

Example 2

[0137] Discharging the Capsules

[0138] A 2 μl sample of the above-described preparate was applied to amicroscopic slide, and the isolated capsules were photographed under alight microscope (Leitz Laborlux S) (See FIG. 3 and FIG. 4). Two μl ofSodium thiocyanate were added to the isolated capsules. Following theNaSCN administration capsules immediately discharged to release theirtubules. The discharged capsules were photographed under a lightmicroscope (FIG. 5).

Example 3

[0139] Inactivation of Capsule-storedpolypeptides

[0140] The temperature range, which is tolerated by Rhopilema nomadica,is between 16° C.-30° C. Therefore, it is possible to performdenaturation and inactivation of an endogenous polypeptide at 45° C.Isolated capsules were incubated for 22 hours in 45° C. Following theheat inactivation process the capsules were intact and their round shapewas unchanged. Moreover, the heated capsules were able to dischargenormally upon treatment with NaSCN.

Example 4

[0141] Altering the Content of the Isolated Capsules

[0142] Isolated capsules were treated with 0.1% Toluidine Blue 0 for 3minutes and than washed 3 times with H₂O. The pigment penetrated theintact capsules and the stained capsules were photographed (FIGS. 6-8, Aarrow). Upon activation with NaSCN the capsules containing the pigmentdischarged normally and released the pigment through the tubule to thesurrounding solution (FIGS. 7-8, B arrow).

[0143] To demonstrate intraepidermal penetration of the delivery tubule,capsules isolated from Rhopilema nomadica were loaded with a pigment(0.1% Toluidine Blue O, MW -306 daltons) and discharged using NaSCN. Asspecifically shown in FIG. 10, which depicts an experiment performed ona 15 micron thick human skin section, following discharge, the tubulepenetrated the stratum corneum and delivered the pigment stored by thecapsule into the squamous cell layer of the epidermis. The tubulepenetration path is depicted in more detail in FIG. 9.

Example 5 Drug Delivery using Stinging Capsules—TheoreticalConsiderations

[0144] Psoralen:

[0145] Psoralen photochemotherapy [psoralen ultraviolet A (PUVA)] playsan important role in dermatological therapeutics, and is utilized fortreating psoriasis and other dermatoses.

[0146] The oral recommended dose for psoralen is approximately 0.5 mg/kgweight. Peak plasma concentration following oral administration variesfrom 2 nanograms/ml to 167 nanograms /ml (mean 56 nanograms /ml).

[0147] As detailed hereinunder, the present invention can be utilized todeliver psoralen in an efficient and accurate manner.

[0148] Since hydra cnidocysts are spherical in shape, with a diameter ofapproximately 10 micrometers, their volume can be calculated as{fraction (4/3)}×π×r³˜4×5³=500 μm³.

[0149] When filled, the capsule contains approximately 0.5 nanograms ofwater. Since a loaded drug, such as psoralen, can occupy 5-10% of thecapsule volume, a single loaded capsule contains about 0.05 nanograms ofthe drug. Since 2×10⁴ to 10 cnidocysts can penetrate a 1 cm region ofskin, the amount of drug which can be delivered by capsules into 1 cm²of skin is: 0.05 nanograms of the drug×2×10⁴ to 10⁶ cnidocysts whichequal to 1-50 μg of the drug per 1 cm² of skin, which is 20-1000 foldhigher than the amount deliverable by oral administration. Thus, thepresent invention can provide targeted delivery of psoralen at highconcentrations while at the same time not inducing toxicity in othertissues of the body.

[0150] Viagra:

[0151] Recently, a new drug was developed to treat male erectiledysfunction: sildenafil citrate (Viagra). The recommended doses for oraladministration for this drug is 25-100 mg once a day. Maximal plasmaconcentration of 440 ng/ml, are reached within 30 to 120 minutesfollowing oral administration of 100 mg. 28

[0152] Using the above described calculations for stingingcells/capsules, targeted delivery of higher concentrations of sildenafilcitrate can be effected.

[0153] Diphenhydramine Hydrochloride:

[0154] Diphenhydramine hydrochloride is an antihistamine used in thetreatment of allergies, stings and skin irritations. An oral dose of 120mg/kg results in a peak plasma concentration of 0.2 μg/ml. 2 hoursfollowing administration. Although the same drug can be administeredtopically by the application of 1-2% diphenhydramine hydrochloride thispharmaceutical formulation is known to have low penetration and thus aslow therapeutic effect.

[0155] Thus, the teachings of the present invention can provide anefficient, rapid and targeted delivery of drugs to treated tissues.

[0156] Although the invention has been described in conjunction withspecific embodiments thereof, it is evident that many alternatives,modifications and variations will be apparent to those skilled in theart. Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims. All publications, patents and patentapplications disclosed therein and/or mentioned in this specificationare herein incorporated in their entirety by reference into thespecification, to the same extent as if each individual publication,patent or patent application was specifically and individually indicatedto be incorporated herein by reference. In addition, citation oridentification of any reference in this application shall not beconstrued as an admission that such reference is available as prior artto the present invention.

REFERENCES

[0157] 1. Anderson, C. L., Canning, E. U., and Okamura, B. (1998). “Atriploblast origin for Myxozoa?” Nature, 392(6674), 346-7.

[0158] 2. Brennecke, T., Gellner, K., and Bosch, T. C. (1998). “The lackof a stress response in Hydra oligactis is due to reduced hsp70 mRNAstability.” Eur J Biochem, 255(3), 703-9.

[0159] 3. Godkenecht, A., and Tardent, P. (1988). “Discharge and mode ofaction of the tentacular nematocysts of Anemonia sulcata (Antozoa:Cnidaria).” Marine Biology, 100, 83-92.

[0160] 4. Heeger, T., Moller, H., and Mroweitz, U. (1992). “Protectionof human skin against jellyfish (Cyanea capillata) stings.” MarineBiology, 113, 669-678.

[0161] 5. Hidaka, M. (1992). “Effects of Ca+ on the volume ofnematocysts isolated from acontia of the sea anemone Calliactistricolor.” Comp Biochem Physiol, 101A(4), 737-741.

[0162] 6. Hidaka, M. (1993). “Mechanism of nematocystn discharge and itscellular control.” Advances in Comparative and Environmemtal Physiology,15, 45-76.

[0163] 7. Holstein, T., and Tardent, P. (1984). “An ultrahigh-speedanalysis of exocytosis: nematocyst discharge.” Science, 223(4638),830-3.

[0164] 8. Lotan, A., Fishman, L., Loya, Y., and Zlotkin, E. (1995).“Delivery of a nematocyst toxin Nature, 375(6531), 456.

[0165] 9. Lotan, A., Fishman, L., and Zlotkin, E. (1996). “Toxincompartmentation and delivery in the Cnidaria: the nematocyst's tubuleas a multiheaded poisonous arrow.” J Exp Zool, 275(6), 444-51.

[0166] 10. Lubbock, R. (1979). “Chemical recognition and nematocyteexitation in sea anemone.” J exp. Biol., 83, 283-292.

[0167] 11. Lubbock, R., and Amos, W. B. (1981). “Removal of boundcalcium from nematocyst contents causes discharge.” Nature, 290(5806),500-1.

[0168] 12. Mariscal, R. N. (1974). Coelenterate biology: reviews and newperspectives, Academic Press, New York.

[0169] 13. Siddall, M. E., Martin, D. S., Bridge, D., Desser, S. S., andCone, D.

[0170] K. (1995). “The demise of a phylum of protists: phylogeny ofMyxozoa and other parasitic cnidaria.” J Parasitol, 81(6), 961-7.

[0171] 14. Smothers, J. F., von Dohlen, C. D., Smith, L. H., Jr., andSpall, R. D. (1994). “Molecular evidence that the myxozoan protists aremetazoans.” Science, 265(5179), 1719-21.

[0172] 15. Tardent, P. (1995). “The cnidarian cnidocyte, a high-techcellular weaponry.” BioEssays, 17(4), 351-362.

[0173] 16. Tardent, P., and Holstein, T. (1982). “Morphology andmorphodynamics of the stenotele nematocyst of Hydra attenuata Pall.(Hydrozoa, Cnidaria).” Cell Tissue Res, 224(2), 269-90.

[0174] 17. Thorington, G. U., and Hessinger, D. A. (1988). “Control ofcnida discharge: I. evidence for two classes of chemoreceptor.” Biol.Bull., 174, 163-171.

[0175] 18. Watson, G. M., and Hessinger, D. (1989). “Cnidocytemechanoreceptors are tuned to the movements of swimming prey bychemoreceptors.” Science, 243, 1585-1591.

[0176] 19. Watson, G. M., and Hessinger, D. A. (1992). “Receptors forN-acetylated sugars may stimulate adenylate cyclase to sensitize andtune mechanoreceptors involved in triggering nematocyst discharge.” ExpCell Res, 198(1), 8-16.

[0177] 20. Weber, J. (1989). “Nematocysts (stinging capsules ofCnidaria) as Donnan-potential- dominated osmotic systems.” Eur JBiochem, 184(2), 465-76.

[0178] 21. Westfall, J A., Bradbury, P. C., and Townsend, J. W. (1983).“Ultrastructure of the dinoflagellate Polykrikos. I. Development of thenematocyst-taeniocyst complex and morphology of the site for extrusion.”J Cell Sci, 63, 245-61.

What is claimed is:
 1. A composition of matter comprising a therapeuticor a cosmetic agent and at least one stinging capsule.
 2. Thecomposition of matter of claim 1, wherein said therapeutic or cosmeticagent is disposed in a liquid surrounding, or stored within, said atleast one stinging capsule.
 3. The composition of matter of claim 1,wherein said therapeutic agent is selected from the group consisting ofa drug, a nucleic acid construct, a vaccine, a hormone, an enzyme and anantibody.
 4. The composition of matter of claim 1, wherein saidtherapeutic agent is a prodrug activatable prior to, during or followingdischarge of said at least one stinging capsule.
 5. The composition ofmatter of claim 1, wherein said cosmetic agent is selected from thegroup consisting of a cosmetic dye, an anti wrinkling agent, ananti-acne agent, a vitamin, a skin peel agent, a hair folliclestimulating agent and a hair follicle suppressing agent.
 6. Thecomposition of matter of claim 1, wherein said at least one stingingcapsule is capable of delivering said therapeutic or cosmetic agent intoa tissue.
 7. The composition of matter of claim 1, wherein an endogenoustoxin naturally stored within said at least one stinging capsule issubstantially non-toxic to mammals.
 8. The composition of matter ofclaim 7, wherein said endogenous toxin is non-functional.
 9. Thecomposition of matter of claim 1, wherein said at least one stingingcapsule is derived from an organism of a class selected from the groupconsisting of Anthozoa, Hydrozoa and Scyphozoa.
 10. The composition ofmatter of claim 1, wherein said at least one stinging capsule is derivedfrom an organism of a phylum selected from the group consisting ofCnidaria, Dinoflagellata and Myxozoa.
 11. The composition of matter ofclaim 1, wherein said stinging capsule forms a part of a stinging cell.12. The composition of matter of claim 11, wherein said stinging cellforms a part of a tentacle derived from an organism of the phylumCnidaria.
 13. A pharmaceutical composition comprising as an activeingredient a therapeutic or cosmetic agent, at least one stingingcapsule and a pharmaceutically acceptable carrier. 14 The pharmaceuticalcomposition of claim 13, wherein said therapeutic or cosmetic agent isdisposed in a liquid surrounding, or stored within, said at least onestinging capsule.
 15. The pharmaceutical composition of claim 13,wherein said therapeutic agent is selected from the group consisting ofa drug, a nucleic acid construct, a vaccine, a hormone, an enzyme and anantibody.
 16. The pharmaceutical composition of claim 13, wherein saidtherapeutic agent is a prodrug activatable prior to, during or followingdischarge of said at least one stinging capsule.
 17. The pharmaceuticalcomposition of claim 13, wherein said cosmetic agent is selected fromthe group consisting of a cosmetic dye, an anti-wrinkling agent, ananti-acne agent, a vitamin, a skin peel agent, a hair folliclestimulating agent and a hair follicle suppressing agent.
 18. Thepharmaceutical composition of claim 13, wherein said at least onestinging capsule is capable of delivering said therapeutic or cosmeticagent into a tissue.
 19. The pharmaceutical composition of claim 13,wherein an endogenous toxin stored within said at least one stingingcapsule is substantially non-toxic to mammals.
 20. The pharmaceuticalcomposition of claim 19, wherein said endogenous toxin isnon-functional.
 21. The pharmaceutical composition of claim 13, whereinsaid at least one stinging capsule is derived from an organism of aclass selected from the group consisting of Anthozoa, Hydrozoa andScyphozoa.
 22. The pharmaceutical composition of claim 13, wherein saidat least one stinging capsule is derived from an organism of a phylumselected from the group consisting of Cnidaria, Dinoflagellata andMyxozoa.
 23. The pharmaceutical composition of claim 13, wherein saidstinging capsule forms a part of a stinging cell.
 24. The pharmaceuticalcomposition of claim 23, wherein said stinging cell forms a part of atentacle derived from an organism of the phylum Cnidaria.
 25. Thepharmaceutical composition of claim 13, wherein said pharmaceuticallyacceptable carrier is selected from the group consisting of an aqueoussolution, a gel, an oil and semi solid formulation.
 26. A deliverydevice comprising: (a) at least one stinging capsule capable ofdelivering upon discharge liquid disposed in or around said at least onestinging capsule into a tissue; and (b) a support being for: (i)supporting said at least one stinging capsule; and (ii) applying said atleast one stinging capsule to an outer surface of said tissue.
 27. Thedevice of claim 26, wherein said at least one stinging capsule isactivated following application of the device to said outer surface ofsaid tissue.
 28. The device of claim 26, further comprising a mechanismfor triggering said discharge of said at least one stinging capsule. 29.The-device of claim 26, wherein said mechanism is selected from thegroup consisting of a chemical triggering mechanism and an electricaltriggering mechanism.
 30. The device of claim 26, wherein said supportis selected from the group consisting of a patch, a foil, a plaster anda film.
 31. The device of claim 26, wherein said at least one stingingcapsule is derived from an organism of a phylum selected from the groupconsisting of Cnidaria, Dinoflagellata and Myxozoa.
 32. The device ofclaim 26, wherein said stinging capsule forms a part of a stinging cell.33. The device of claim 32, wherein said stinging cell forms a part of atentacle derived from an organism of the phylum Cnidaria.
 34. The deviceof claim 26, wherein an endogenous toxin stored within said at least onestinging capsule is substantially non-toxic to mammals.
 35. The deviceof claim 34, wherein said endogenous toxin is non-functional.
 36. Thedevice of claim 26, wherein said at least one stinging capsule isderived from an organism of a class selected from the group consistingof Anthozoa, Hydrozoa and Scyphozoa.
 37. A method of delivering atherapeutic or a cosmetic agent into a tissue, the method comprising thesteps of: (a) applying a composition of matter including the therapeuticor cosmetic agent disposed in or around at least one stinging capsule toan outer surface of the tissue; and (b) triggering a discharge of saidat least one stinging capsule to thereby deliver the therapeutic or thecosmetic agent into the tissue.
 38. The method of claim 37, wherein anendogenous toxin stored within said at least one stinging capsule issubstantially non-toxic to mammals.
 39. The method of claim 38, whereinsaid endogenous toxin is non-functional.
 40. The method of claim 37,wherein said at least one stinging capsule is derived from an organismof a class selected from the group consisting of Anthozoa, Hydrozoa andScyphozoa.
 41. The method of claim 37, wherein said therapeutic agent isselected from the group consisting of a drug, a nucleic acid construct,a vaccine, a hormone, an enzyme and an antibody.
 42. The method of claim37, wherein said therapeutic agent is a prodrug activatable prior to,during or following discharge of said at least one stinging capsule. 43.The method of claim 37, wherein said cosmetic agent is selected from thegroup consisting of a cosmetic dye, an anti-wrinkling agent, a vitamin,a skin peel agent, a hair follicle stimulating agent and a hair folliclesuppressing agent.
 44. The method of claim 37, wherein said at least onestinging capsule is derived from an organism of a phylum selected fromthe group consisting of Cnidaria, Dinoflagellata and Myxozoa.
 45. Themethod of claim 37, wherein said stinging capsule forms a part of astinging cell.
 46. The method of delivery of claim 45, wherein saidstinging cell forms a part of a tentacle derived from an organism of thephylum Cnidaria. 47 The method of delivery of claim 37, wherein the stepof triggering is effected by a change in pH, a chemical substance, amechanical force or contact between said at least one stinging capsuleand said outer surface of the tissue.
 48. A method of delivering atherapeutic or a cosmetic agent into a tissue, the method comprising thesteps of: (a) applying a composition including, as an active ingredient,at least one therapeutic or cosmetic agent onto an outer surface of thetissue; (b) applying at least one stinging capsule to said outer surfaceof the tissue; and (c) triggering a discharge of said at least onestinging capsule to thereby deliver the therapeutic or the cosmeticagent into the tissue.
 49. The method of claim 48, wherein an endogenoustoxin stored within said at least one stinging capsule is substantiallynon-toxic to mammals.
 50. The method of claim 49, wherein saidendogenous toxin is non-functional.
 51. The method of claim 48, whereinsaid at least one stinging capsule is derived from an organism of aclass selected from the group consisting of Anthozoa, Hydrozoa andScyphozoa.
 52. The method of claim 48, wherein said therapeutic agent isselected from the group consisting of a drug, a nucleic acid construct,a vaccine, a hormone an enzyme and an antibody.
 53. The method of claim48, wherein said therapeutic agent is a prodrug activatable prior to,during or following discharge of said at least one stinging capsule. 54.The method of claim 48, wherein said cosmetic agent is selected from thegroup consisting of a cosmetic dye, a vitamin, a skin peel agent, a hairfollicle stimulating agent and a hair follicle suppressing agent. 55.The method of delivery of claim 48, wherein said at least one stingingcapsule is derived from an organism of a phylum selected from the groupconsisting of Cnidaria, Dinoflagellata and Myxozoa.
 56. The method ofclaim 48, wherein said stinging capsule forms a part of a stinging cell.57. The method of delivery of claim 56, wherein said stinging cell formsa part of a tentacle derived from an organism of the phylum Cnidaria. 58The method of delivery of claim 48, wherein the step of triggering iseffected by a change in pH, a chemical substance, a mechanical force orcontact between said at least one stinging capsule and said outersurface of the tissue.
 59. A method of preparing a delivery device, themethod comprising the steps of: (a) isolating an intact stinging cell orstinging capsule from an organism; and (b) treating said stinging cellor said stinging capsule under conditions which inactivate an endogenoustoxin stored therein yet do not trigger discharge or breakdown of saidstinging cell or said stinging capsule, to thereby obtain the deliverydevice.
 60. The method of claim 59, wherein said organism is of a phylumselected from the group consisting of Cnidaria, Dinoflagellata andMyxozoa.
 61. The method of claim 59, wherein step (b) is effected byincubating said stinging cell or said stinging capsule at a temperatureof 35-45° C. for at least two hours.
 62. A delivery device comprising anisolated stinging cell, wherein an endogenous toxin stored therein isnon-functional.
 63. A delivery device comprising an isolated stingingcapsule, wherein an endogenous toxin stored therein is non-functional.64. A composition of matter comprising a therapeutic or a cosmetic agentand at least one isolated stinging capsule.
 65. A pharmaceuticalcomposition comprising as an active ingredient a therapeutic or cosmeticagent, at least one isolated stinging capsule and a pharmaceuticallyacceptable carrier.
 66. A delivery device comprising: (a) at least oneisolated stinging capsule capable of delivering upon discharge liquiddisposed in or around said at least one stinging capsule into a tissue;and (b) a support being for: (i) supporting said at least isolated onestinging capsule; and (ii) applying said at least one stinging capsuleto an outer surface of said tissue.
 67. A method of delivering atherapeutic or a cosmetic agent into a tissue, the method comprising thesteps of: (a) applying a composition of matter including the therapeuticor cosmetic agent disposed in or around at least one isolated stingingcapsule to an outer surface of the tissue; and (b) triggering adischarge of said at least one isolated stinging capsule to therebydeliver the therapeutic or the cosmetic agent into the tissue.
 68. Amethod of delivering a therapeutic or a cosmetic agent into a tissue,the method comprising the steps of: (a) applying a compositionincluding, as an active ingredient, at least one therapeutic or cosmeticagent onto an outer surface of the tissue; (b) applying at least oneisolated stinging capsule to said outer surface of the tissue; and (c)triggering a discharge of said at least one isolated stinging capsule tothereby deliver the therapeutic or the cosmetic agent into the tissue.69. A delivery device comprising: (a) a plurality of stinging capsulescapable of delivering upon discharge a dye disposed in or around saidplurality of stinging capsules into a tissue; and (b) a support beingfor: (i) supporting said plurality of stinging capsules; and (ii)applying said plurality of stinging capsules to an outer surface of saidtissue.
 70. The delivery device of claim 69, wherein said plurality ofstinging capsules are attached to a surface of said support in apredetermined pattern, such that application of said surface of saidsupport to said tissue region and activation of said plurality ofstinging capsules containing or surrounded by said dye -forms apredetermined dye pattern within said tissue.
 71. The delivery device ofclaim 69, wherein said dye is a cosmetic dye.
 72. The delivery device ofclaim 69, wherein said support is selected from the group consisting ofa patch, a foil, a plaster and a film.